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- Publisher Website: 10.1074/jbc.M000039200
- Scopus: eid_2-s2.0-0034613385
- PMID: 10843986
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Article: Requirement of Ras/MAPK pathway activation by transforming growth factor β for transforming growth factor β1 production in a Smad-dependent pathway
Title | Requirement of Ras/MAPK pathway activation by transforming growth factor β for transforming growth factor β1 production in a Smad-dependent pathway |
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Authors | |
Issue Date | 2000 |
Publisher | American Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/ |
Citation | Journal Of Biological Chemistry, 2000, v. 275 n. 40, p. 30765-30773 How to Cite? |
Abstract | Our previous results have shown that transforming growth factor β (TGFβ) rapidly activates Ras, as well as both ERKs and SAPKs. In order to address the biological significance of the activation of these pathways by TGFβ, here we examined the role of the Ras/MAPK pathways and the Smads in TGFβ3 induction of TGFβ1 expression in untransformed lung and intestinal epithelial cells. Expression of either a dominant-negative mutant of Ras (RasN17) or a dominant-negative mutant of MKK4 (DN MKK4), or addition of the MEK1 inhibitor PD98059, inhibited the ability of TGFβ3 to induce AP-1 complex formation at the TGFβ1 promoter, and the subsequent induction of TGFβ1 mRNA. The primary components present in this TGFβ3-inducible AP-1 complex at the TGFβ1 promoter were JunD and Fra-2, although c-Jun and FosB were also involved. Furthermore, deletion of the AP-1 site in the TGFβ1 promoter or addition of PD98059 inhibited the ability of TGFβ3 to stimulate TGFβ1 promoter activity. Collectively, our data demonstrate that TGFβ3 induction of TGFβ1 is mediated through a signaling cascade consisting of Ras, the MAPKKs MKK4 and MEK1, the MAPKs SAPKs and ERKs, and the specific AP-1 proteins Fra-2 and JunD. Although Smad3 and Smad4 were not detectable in TGFβ3-inducible AP-1 complexes at the TGFβ1 promoter, stable expression of dominant-negative Smad3 could significantly inhibit the ability of TGFβ3 to stimulate TGFβ1 promoter activity. Transient expression of dominant-negative Smad4 also inhibited the ability of TGFβ3 to transactivate the TGFβ1 promoter. Thus, although the Ras/MAPK pathways are essential for TGFβ3 induction of TGFβ1, Smads may only contribute to this biological response in an indirect manner. |
Persistent Identifier | http://hdl.handle.net/10722/171684 |
ISSN | 2020 Impact Factor: 5.157 2023 SCImago Journal Rankings: 1.766 |
ISI Accession Number ID | |
References |
DC Field | Value | Language |
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dc.contributor.author | Yue, J | en_US |
dc.contributor.author | Mulder, KM | en_US |
dc.date.accessioned | 2012-10-30T06:16:20Z | - |
dc.date.available | 2012-10-30T06:16:20Z | - |
dc.date.issued | 2000 | en_US |
dc.identifier.citation | Journal Of Biological Chemistry, 2000, v. 275 n. 40, p. 30765-30773 | en_US |
dc.identifier.issn | 0021-9258 | en_US |
dc.identifier.uri | http://hdl.handle.net/10722/171684 | - |
dc.description.abstract | Our previous results have shown that transforming growth factor β (TGFβ) rapidly activates Ras, as well as both ERKs and SAPKs. In order to address the biological significance of the activation of these pathways by TGFβ, here we examined the role of the Ras/MAPK pathways and the Smads in TGFβ3 induction of TGFβ1 expression in untransformed lung and intestinal epithelial cells. Expression of either a dominant-negative mutant of Ras (RasN17) or a dominant-negative mutant of MKK4 (DN MKK4), or addition of the MEK1 inhibitor PD98059, inhibited the ability of TGFβ3 to induce AP-1 complex formation at the TGFβ1 promoter, and the subsequent induction of TGFβ1 mRNA. The primary components present in this TGFβ3-inducible AP-1 complex at the TGFβ1 promoter were JunD and Fra-2, although c-Jun and FosB were also involved. Furthermore, deletion of the AP-1 site in the TGFβ1 promoter or addition of PD98059 inhibited the ability of TGFβ3 to stimulate TGFβ1 promoter activity. Collectively, our data demonstrate that TGFβ3 induction of TGFβ1 is mediated through a signaling cascade consisting of Ras, the MAPKKs MKK4 and MEK1, the MAPKs SAPKs and ERKs, and the specific AP-1 proteins Fra-2 and JunD. Although Smad3 and Smad4 were not detectable in TGFβ3-inducible AP-1 complexes at the TGFβ1 promoter, stable expression of dominant-negative Smad3 could significantly inhibit the ability of TGFβ3 to stimulate TGFβ1 promoter activity. Transient expression of dominant-negative Smad4 also inhibited the ability of TGFβ3 to transactivate the TGFβ1 promoter. Thus, although the Ras/MAPK pathways are essential for TGFβ3 induction of TGFβ1, Smads may only contribute to this biological response in an indirect manner. | en_US |
dc.language | eng | en_US |
dc.publisher | American Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/ | en_US |
dc.relation.ispartof | Journal of Biological Chemistry | en_US |
dc.subject.mesh | Animals | en_US |
dc.subject.mesh | Bacterial Proteins - Metabolism | en_US |
dc.subject.mesh | Base Sequence | en_US |
dc.subject.mesh | Cell Line | en_US |
dc.subject.mesh | Culture Media, Serum-Free | en_US |
dc.subject.mesh | Dna-Binding Proteins - Metabolism | en_US |
dc.subject.mesh | Enzyme Activation | en_US |
dc.subject.mesh | Enzyme Inhibitors - Pharmacology | en_US |
dc.subject.mesh | Epithelial Cells - Metabolism | en_US |
dc.subject.mesh | Flavonoids - Pharmacology | en_US |
dc.subject.mesh | Fos-Related Antigen-2 | en_US |
dc.subject.mesh | Genes, Dominant | en_US |
dc.subject.mesh | Genes, Ras - Genetics | en_US |
dc.subject.mesh | Intestines - Metabolism | en_US |
dc.subject.mesh | Kinetics | en_US |
dc.subject.mesh | Liver - Metabolism | en_US |
dc.subject.mesh | Luciferases - Metabolism | en_US |
dc.subject.mesh | Lung - Metabolism | en_US |
dc.subject.mesh | Map Kinase Kinase 4 | en_US |
dc.subject.mesh | Map Kinase Signaling System | en_US |
dc.subject.mesh | Mink | en_US |
dc.subject.mesh | Mitogen-Activated Protein Kinase Kinases - Genetics | en_US |
dc.subject.mesh | Molecular Sequence Data | en_US |
dc.subject.mesh | Mutagenesis, Site-Directed | en_US |
dc.subject.mesh | Plasmids - Metabolism | en_US |
dc.subject.mesh | Promoter Regions, Genetic | en_US |
dc.subject.mesh | Protein Binding | en_US |
dc.subject.mesh | Proto-Oncogene Proteins C-Fos | en_US |
dc.subject.mesh | Proto-Oncogene Proteins C-Jun - Metabolism | en_US |
dc.subject.mesh | Rna, Messenger - Metabolism | en_US |
dc.subject.mesh | Rats | en_US |
dc.subject.mesh | Ribonucleases - Metabolism | en_US |
dc.subject.mesh | Signal Transduction | en_US |
dc.subject.mesh | Smad3 Protein | en_US |
dc.subject.mesh | Smad4 Protein | en_US |
dc.subject.mesh | Time Factors | en_US |
dc.subject.mesh | Trans-Activators - Metabolism | en_US |
dc.subject.mesh | Transcription Factor Ap-1 - Metabolism | en_US |
dc.subject.mesh | Transcription Factors - Metabolism | en_US |
dc.subject.mesh | Transfection | en_US |
dc.subject.mesh | Transforming Growth Factor Beta - Biosynthesis - Metabolism | en_US |
dc.subject.mesh | Transforming Growth Factor Beta1 | en_US |
dc.subject.mesh | Transforming Growth Factor Beta3 | en_US |
dc.subject.mesh | Ras Proteins - Physiology | en_US |
dc.title | Requirement of Ras/MAPK pathway activation by transforming growth factor β for transforming growth factor β1 production in a Smad-dependent pathway | en_US |
dc.type | Article | en_US |
dc.identifier.email | Yue, J:jyue@hku.hk | en_US |
dc.identifier.authority | Yue, J=rp00286 | en_US |
dc.description.nature | link_to_subscribed_fulltext | en_US |
dc.identifier.doi | 10.1074/jbc.M000039200 | - |
dc.identifier.pmid | 10843986 | - |
dc.identifier.scopus | eid_2-s2.0-0034613385 | en_US |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-0034613385&selection=ref&src=s&origin=recordpage | en_US |
dc.identifier.volume | 275 | en_US |
dc.identifier.issue | 40 | en_US |
dc.identifier.spage | 30765 | en_US |
dc.identifier.epage | 30773 | en_US |
dc.identifier.isi | WOS:000089762700006 | - |
dc.publisher.place | United States | en_US |
dc.identifier.scopusauthorid | Yue, J=7101875828 | en_US |
dc.identifier.scopusauthorid | Mulder, KM=7005187184 | en_US |
dc.identifier.issnl | 0021-9258 | - |